DESCRIPTION: It is estimated that 47.5 million people worldwide are currently living with dementia or some form of cognitive impairment. With time, this number is expected to surge as the global population of individuals 60 years of age triples. Thus, a better understanding of the risk factors for cognitive impairment will be critical for measures aimed at reducing current and future global morbidity. Fine particle (PM2.5) air pollution is an important risk factor for cognitive impairment, and it is estimated that at least 2.1 million lives could be saved annually if PM2.5 guidelines were adhered to worldwide. Moreover, the fact that elderly individuals are particularly susceptible to PM2.5-related cognitive impairment further classifies it as a risk factor we can not afford to ignore. Although limiting PM2.5 exposure should remain the primary goal for reducing toxicity, regulating such exposures has proved difficult and millions of people continue to be exposed to PM2.5 daily. Consequently, understanding how PM2.5 can affect cognition is essential for the development of interventions for populations that have already been and continue to be exposed. One promising tool to improve upon existing knowledge in these areas is DNA methylation age (DNAm-age) ? a novel epigenetic marker of biological age. Research from our group has demonstrated robust associations between DNAm-age and long-term total PM2.5 exposure levels. Moreover, we also have findings that show that the association between PM2.5 and DNAm-age can be modified by polymorphisms in genes involved in endothelial function, a major pathway already implicated in multiple forms of cognitive impairment. Other groups have already associated increases in DNAm-age with deficits in cognition in Alzheimer?s disease and elderly Scottish populations. However, no existing studies have examined DNAm-age in the context of PM2.5-related cognition in a healthy North American elderly population. The proposed project uses a novel integration of epidemiologic methods and participants from the United States Veterans Affairs Normative Aging Study (NAS) ? a large ongoing longitudinal cohort study of aging individuals established in 1963 ? to address this research gap. Overall, we hypothesize that DNAm-age can be used as a sensitive biomarker of endothelial-related cognitive changes. Aim 1 of the proposal will test the prediction that DNAm-age is associated with endothelial function in the elderly. Given that DNAm-age is a tissue independent measure and that blood DNAm-age is known to be highly correlative of brain DNAm-age, aim 2 will test the prediction that increasing blood DNAm-age will be associated with significantly greater deficits in cognitive function. Ultimately, the successful completion of this research will be the very first steps in understanding if DNAm-age can be used as sensitive biomarker of pre- clinical endothelial-related cognitive changes while furthering the understanding of PM2.5-related cognitive impairment.